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Review

Why Are Computational Neuroscience and Systems


Biology So Separate?
Erik De Schutter1,2*
1 Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Japan, 2 Theoretical Neurobiology, University of Antwerp, Antwerp, Belgium

cosyne.org). Alternatively, computational neuroscience is about


the use of computational approaches to investigate the properties
of nervous systems at different levels of detail [810]. Strictly
speaking, this implies simulation of numerical models on
computers, but usually analytical models are also included (e.g.,
the material covered in [9]), and experimental verification of
models is an important issue [11]. Sometimes this modeling is
quite data driven and may involve cycling back and forth between
experimental and computational methods [12]. A typical venue is
the Computational Neuroscience Meeting (http://www.cnsorg.
org/) and user meetings of specific neural simulator packages.
Although these two opposing views are often swept under the
carpet, and many scientists attend both conferences mentioned,
they are reflected in partially separate communities and sometimes
lead to heated debate about how the field should be defined.
Similarly, systems biology has also been described in multiple
ways. For some it is the integrative study of the interactions
between different components of biological systems, and how such
interactions give rise to the function and behavior of a system. This
approach is, for example, typified by the (Seattle) Institute for
Systems Biology (http://www.systemsbiology.org/). For others, it
is an approach using theory and computational modeling in close
interaction with experimental verification to understand the
dynamical behavior of biological systems [13,14], sometimes also
called computational biology. The major meeting in systems
biology is the International Conference on Systems Biology
(http://www.icsb-2007.org/).
In the rest of this perspective I will not dwell on these
distinctions, and will instead emphasize the computational side of
both fields.

Abstract: Despite similar computational approaches,


there is surprisingly little interaction between the
computational neuroscience and the systems biology
research communities. In this review I reconstruct the
history of the two disciplines and show that this may
explain why they grew up apart. The separation is a pity,
as both fields can learn quite a bit from each other.
Several examples are given, covering sociological, software technical, and methodological aspects. Systems
biology is a better organized community which is very
effective at sharing resources, while computational
neuroscience has more experience in multiscale modeling
and the analysis of information processing by biological
systems. Finally, I speculate about how the relationship
between the two fields may evolve in the near future.

Introduction
As a computational neuroscientist, I was quite enthusiastic when
the systems biology field appeared on the international scientific
agenda of the late nineties. Both fields strongly emphasize the use of
computational modeling to predict and investigate the properties of
biological systems, and I hoped that they would interact closely and
strengthen each other. In fact, some of the early initiatives in
systems biology were led by computational neuroscientists [1].
Unfortunately this is not what happened: systems biology went its
own way and now the two disciplines largely ignore each other. A
glimmer of hope is this journal, PLoS Computational Biology, which
has attracted both in its editorial board and in the papers it
publishes a representative mix of both fields. In this review I will
explore what are the most likely reasons for the separation between
the two disciplines and argue that this is to their detriment, as they
have a lot to learn from each other. I will focus more on
computational neuroscience, as I know this field best.

Origins of Computational Neuroscience


The lack of interaction between the two disciplines can be most
easily understood from an historical perspective. Well see that
important present-day differences originated in the early days of
the respective fields.
It is common to trace the origin of computational neuroscience
to the mathematical model Alan L. Hodgkin and Andrew F.

What Are Computational Neuroscience and


Systems Biology?
Interestingly, for both fields the exact definition of what they are
about and whether they are defined by computational methods is
in dispute (e.g., see the respective entries in wikipedia). They can
be defined as either fields of study or as a computational paradigm.
In the case of computational neuroscience, the term is often used
to denote theoretical approaches in neuroscience, focusing on how
the brain computes information [2]. Examples are the search for
the neural code [3], using experimental, analytical, and (to a
limited degree) modeling methods, or theoretical analysis of
constraints on brain architecture and function [4,5]. This
theoretical approach is closely linked to systems neuroscience
[6,7], which studies neural circuit function, most commonly in
awake, behaving intact animals, and has no relation at all to
systems biology. A major venue for this community is the
Computational and Systems Neuroscience Meeting (http://
PLoS Computational Biology | www.ploscompbiol.org

Citation: De Schutter E (2008) Why Are Computational Neuroscience and


Systems Biology So Separate? PLoS Comput Biol 4(5): e1000078. doi:10.1371/
journal.pcbi.1000078
Editor: Karl J. Friston, University College London, United Kingdom
Published May 30, 2008
Copyright: ! 2008 Erik De Schutter. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Funding: Okinawa Institute of Science and Technology Promotion Company
(OISTPC), and Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO).
Competing Interests: The authors have declared that no competing interests
exist.
* E-mail: erik@oist.jp

May 2008 | Volume 4 | Issue 5 | e1000078

Systems meeting, http://nips.cc/, in 1987), summer courses


(Methods in Computational Neuroscience at Woods Hole in
1988), standard neural simulator software packages like GENESIS
and NEURON [43,44]; and the first textbook appeared [45].

Huxley [15] developed of the squid giant axon action potential,


though one could also argue for the introduction of the integrateand-fire neuron by Louis Lapicque one century ago [16,17]. But
while neither paper promoted the use of computational methods in
neuroscience directly, the Hodgkin and Huxley model remains a
cornerstone of the field and is, surprisingly, still extensively used in
its original form [1821].
The next big step was the work of Wilfrid Rall, who used
mathematical approaches based on cable theory to show that the
dendritic arborizations of neurons strongly affect processing of
synaptic input [2224]. He pioneered the use of digital computers
in neuroscience and developed the discretized version of cable
theory, compartmental modeling [24], which forms the basis for
some of the most widely used software packages in computational
neuroscience (such as GENESIS [25] and NEURON [26]). His
contribution is historically interesting for two additional reasons:
his conflict with experimental neuroscientists and the attention to
the spatial domain.
Before Rall, neurons were assumed to be isopotential and the
electrophysiological importance of dendrites was ignored [27].
Modelers removed the spatial dimension and focused only on
temporal aspects of the input-output properties, starting with the
introduction of the point unit by McCulloch and Pitts [28].
Similarly, experimentalists, who just started making intracellular
recordings, assumed that current was mostly confined to the soma
(e.g., [29]). This set the scene for the famous conflict between John
Eccles and Wilfrid Rall [30] about the need to take current flow to
dendrites into account when interpreting data recorded in the soma
[31]. Not only did this lead to almost a decade of conflict with Eccles,
during which period the latter received the Nobel prize together with
Hodgkin and Huxley in 1963, but Rall experienced real problems in
getting his early work published [30]. In general, the rather
elaborate and sophisticated considerations [32] introduced by Rall
had only a limited impact on the thinking of contemporary
neuroscientists. It wasnt until the early seventies that key concepts
introduced by Rall, like spatial summation and dendritic attenuation
of synaptic input [23,24], which are now part of core curricula in
neuroscience, became commonplace. The general skepticism of
experimental neuroscientists toward the validity of theoretical and
modeling approaches compared to the experimental method
remains a challenge to the field of computational neuroscience.
Though the attitude has improved, it will take a long time before
theory is taken as seriously in neuroscience as in physics, and even
now many experimental neuroscientists expose rather nave views on
the role of theory. One of the reasons why computational
neuroscientists showed so little interest in the emerging field of
systems biology a decade ago may be that they were more interested
in trying to integrate themselves into mainstream neuroscience.
There is no need to describe the further history of the field in
detail. Ralls work influenced both mathematicians [3335] and
physiologists [36] so that by the mid-seventies some authors started
publishing fairly complex single neuron models and using them in
neural network modeling [37,38]. In general these modelers
benefited from the fact that neurophysiology has always been a
very quantitative science, providing accurate measurements of
currents, voltages, spike trains, etc. Theoretical neuroscience also
has many fathers, including Donald Hebb [39] and Norbert
Wiener [40], followed by Frank Rosenblatt [41] for the machine
learning/connectionist branch, and Werner Reichardt [42] for the
neural coding branch.
The term computational neuroscience appeared in the second
half of the eighties [10]. Many seminal initiatives were started around
that time: graduate programs (for example the CNS program at
Caltech in 1986), meetings (the Neural Information Processing
PLoS Computational Biology | www.ploscompbiol.org

Origins of Systems Biology


Traditionally it is assumed that systems biology originated in the
late nineties. This neglects the fact that Mihajlo D. Mesarovic,
Ludwig von Bertalanffy, and their colleagues already proposed
applying general systems theory to biology in the sixties [46,47],
though with limited impact. Also important was the ground-laying
work performed by several mathematical modeling communities,
including those in metabolic analysis [48,49], physical chemistry
[50], cardiac physiology [15,51], and developmental biology
[52,53]. Unfortunately, most of these efforts were rather isolated,
with little influence on the research agendas of the respective
experimental communities.
The genomics revolution of the nineties [54], closely followed by
proteomics [55] and other omics fields, led to a paradigm shift in
biology that caused the rediscovery and popularization of systems
biology separately and simultaneously by Lee Hood and Hiroaki
Kitano in the late nineties [14,56,57]. First, technological
innovations turned the affected areas into data-driven discovery
sciences [56], where complete listings of all the entities of a system
(genes, proteins, ) became possible, and, moreover, these listings
were shared easily through databases [58]. In other words, an
exhaustive, detailed description of the system became not only
feasible but was in its overwhelming complexity often the primary
data available. This necessitated new, more integrative approaches
to analyzing and manipulating the data, for which systems level
theory was the best tool. Second, the same innovations made it
also much easier to measure biological and chemical properties
quantitatively, producing the numbers needed for computational
modeling. Importantly, leading biologists like Lee Hood promoted
from the beginning the computational approach as an essential
tool to investigate the dynamics of the systems studied. The new
field of systems biology leveraged and incorporated most of the
preceding work in mathematical biology in a short time, with the
notable exception of computational neuroscience.

Difference in Respective Cultures


The separate origins of the two fields, with computational
neuroscience clearly being the more old-fashioned one, can
explain several major differences in their scientific cultures. I will
emphasize two: data-driven modeling and community based
standards development.
As already mentioned, systems biology mostly operates in a
data-rich environment, where the challenge is more to isolate the
important from the less important than to infer unknowns. This is
very different from the situation in neuroscience where data is
usually incomplete and a lot of guesswork is needed. An example
to clarify this issue is the different approaches to networks. A very
active area in systems biology is the application of graph theory
[59] to analyze the topologies of detailed genetic and molecular
networks, as this may shed light on the organizing principles
governing their dynamics [6062]. While such approaches are also
used in neuroscience [63], most of the work on neural networks
simulates randomly connected networks to investigate their
dynamics [64,65]. This approach may in some cases simplify
analysis [66], but in general it is necessitated by a lack of data. For
most neural networks, detailed connectivity schemes are unknown
and methods to collect the data are still being developed [67,68].
In general, computational neuroscience lacks the databases
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necessary for data-driven modeling, and the databases available


tend to suffer from a lack of data (with of course the notable
exception of the Allen Brain Atlas at http://www.brain-map.org/,
which is genomics). The reasons for this deplorable situation have
been described elsewhere [69,70] and include sociological aspects,
but also the overall organization of neuroscience research, which is
often fragmented, small-scale, and lacks standardized data
annotation [71].
Systems biology inherited the large-scale collaborative approaches common in industrialized genomics and benefited
from the availability of more mature software development tools in
the late nineties [72]. This is a real advantage, as many established
computational neuroscience software is shackled by legacy code
(such as GENESIS [25], at http://www.genesis-sim.org/, and
NEURON [26], at http://www.neuron.yale.edu/neuron/). Even
worse, large communities, especially in neural network modeling,
still use homegrown software that is simply not available
electronically. Otherwise, the respective software landscapes may
seem similar as one can find in either field both open source (the
already mentioned GENESIS and NEURON; E-Cell [73] at
http://e-cell.org/ecell/) and copyrighted packages (Mcell at
http://www.mcell.cnl.salk.edu/ and NeuroConstruct [74] at
http://www.physiol.ucl.ac.uk/research/silver_a/neuroConstruct/;
Virtual Cell [75] at http://www.vcell.org/). The differences
become more obvious if one looks at some of the infrastructure
supporting this software development, in particular the development of standards. For example, compare the terminology efforts
of the Neuroscience Information Framework (NIF at http://
neurogateway.org/catalog/goto.do?page = .terminology) with the
Systems Biology Markup Language (SBML [76] at http://www.
sbml.org/). The first is an attempt by the neuroinformatics field to
set up data annotation standards for neuroscience, and also covers
computational neuroscience. Despite the fact that several terminology workshops have been organized since 2004, it is very
difficult to find any online information on this project. Moreover, it
is unclear how it relates to the NeuroML ([77] at http://www.
neuroml.org/) initiative, which is developing common data formats
and associated metadata infrastructure for computational neuroscience. Contrast the top-down, secretive approach of NIF
terminology with SBML, which has become a de facto standard
of systems biology. This standard model description language
encapsulates the full domain of biochemical reaction systems in a
single mixed pool. An important reason for SBMLs success is the
bottom-up approach used in its development, involving all
stakeholders in active discussions about the standard and making
very effective use of Web-based collaboration tools. This community-based development model is of course copied from the open
source movement (note the similarities with Linux) and has resulted
in a much wider acceptance of SBML than the competing standard
(CellML [78] at http://www.cellml.org/), which is based at a single
institution. The success of SBML should be a model for
(computational) neuroscience in how to develop standards in a
cheap and effective manner, but such a change will not come easy as
it goes against the current insular culture of the field.
Of course SBML can also be improved; i.e., despite its wide
implementation, few software packages support all of SBML and
many limit SBML support to write-only mode. For application in
neuroscience, the current version lacks provisions for defining
geometry or spatial coordinates, which are necessary to simulate
biochemical models of synapses that include detailed 3-D
geometry at the submicroscopic level [7981], but this should be
solved in the next version.
SBML has not prevented a proliferation of software programs
executing very similar tasks (http://www.sbml.org/SBML_SoftwarPLoS Computational Biology | www.ploscompbiol.org

e_Guide), exactly like what happened in computational neuroscience


[82,83]. But the use of SBML strongly enhances portability of
models between different programs and therefore promotes sharing
and reuse of models through deposition in the BioModels Database
(http://www.ebi.ac.uk/biomodels/). An interesting reuse has been
to simulate hundreds of models to validate and benchmark
simulators (http://www.biouml.org/biomodels.shtml). The situation
is very different in computational neuroscience where only now,
more than 20 years after their origin, the interoperability between
two major neural simulators is being implemented [74,84] and
network simulation packages are being benchmarked [82]. As a
consequence, sharing of neural models is still limited and not
obligatory, though the model database ModelDB (http://senselab.
med.yale.edu/modeldb/) [85] is gaining impact. But almost every
computational neuroscientist will have experienced the frustration of
trying to recode a model from the literature first-hand. Systems
biology therefore serves as an example of how a scientific community
can implement standards in a universally accepted manner and how
to enforce publishing of model code and scripts.

What Has Computational Neuroscience To Offer?


There are many areas where systems biology and computational
neuroscience have achieved comparable levels of expertise, i.e., in
automated parameter searching [86,87]. But because it is a more
mature field, computational neuroscience has more extensive
experience in some specific topics [88].
A major strength of computational neuroscience is the
accumulated knowhow in simulator software development,
especially for multiscale modeling. The latter started when the
cable equation introduced by Rall [24] was combined with
Hodgkin-Huxley type models [15] of voltage-gated channels to
model the effect of neural excitability on synaptic integration
[37,38,89,90], but now extends from molecules to large neural
networks. To support these simulations, both very specialized and
general purpose simulators have been developed. For example, the
multiscale simulator GENESIS allows us to include detailed
biochemical pathways simulations, using the kinetikit module [91]
(http://www.ncbs.res.in/,bhalla/kkit/), into morphologically detailed neuron models [92] or large neural network models [93].
An interesting specialized simulator is Mcell [79,80], which
should be of great interest to the systems biology community. This
mature and well-supported program is highly optimized to
simulate reactiondiffusion systems in reconstructed 3D environments. Based on ray-tracing methods, it was first applied to
extracellular diffusion and interaction with membrane bound
receptors, in particular in the synaptic cleft [94], but Mcell3 now
allows simulation of intracellular reactiondiffusion systems in
great detail [79]. As already pointed out above, Mcell is not
compatible with SBML version 2.
In other cases the interest may not be so much to apply the
simulator itself, but to learn from the technical software expertise
developed in building it. For example, the NEST simulator ([95] at
http://www.nest-initiative.org/) was created to model very large
neural networks consisting of fairly simple neuron models. The
NEST developers have achieved a deep understanding of distributed
event modeling, leading to very efficient, supralinear parallelization
of their algorithms [96]. Similarly, it can be expected that the
software development done by the Blue Brain project (http://
bluebrain.epfl.ch/), which aims to build an extremely detailed tissue
model of a cortical column containing tens of thousands of complex
neuron models [97,98], may be of interest to systems biologists.
A challenge common to both fields is how to understand
information processing by biological systems. While genetics has
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as too specialized, while many computational neuroscientists have


little interests in genes and molecules.
However, I do not believe that the current situation will persist.
Faced with the big disparity in funding levels, and even the
abolishment of neuroscience specific programs like the Human
Brain Project [113], there will be increasing pressure on the
computational neuroscientists who would fit most easily into the
systems biology world, those modeling at the subcellular and
cellular levels, to cross over. Maybe this is already happening.
Organizers of meetings like the CNS meeting and of specialized
computational neuroscience summer courses (http://www.neuroinf.org/courses/ and http://www.irp.oist.jp/ocnc/) have been
noticing a decrease in participants interested in cellular modeling
and a shift toward networks and information coding. This has
often been attributed to the increased use of cellular modeling
techniques by experimental neurophysiologists [114], who are less
motivated to attend these events. But an alternative hypothesis is
that this reflects a shift of young scientists interested in cellular
modeling toward systems biology. If this interpretation is correct,
the field of computational neuroscience as we know it will
gradually disappear. The more theoretical part, concerned with
cognitive operations and the neural code, may then merge further
into systems neuroscience, while the bottom-up modelers will
become systems biologists. This would not be a very satisfactory
outcome, as it will still leave a lot of scientists hanging in between,
like bottom-up modelers who want to study cognitive phenomena
(see the Blue Brain project).
To prevent this outcome, the field of computational neuroscience will have to explicitly reach out to systems biology and to
adapt to some of its conventions, as mentioned before. Eventually,
it could then form a bridge between systems biology and
neuroscience. A related question, of course, is the stability of the
neuroscience field itself and whether it will become a data-driven
discovery science [56,115]. But even if neuroscience would change
to such a degree, its strong emphasis on the understanding of
human cognition will keep neuroscience distinct from the rest of
biology.

progressed from the simplistic view of the genome as a map to


more complex gene networks, the types of analysis used do not
focus much on the information content. Both genetic and
molecular networks are most commonly analyzed using dynamical
systems [99101] or graph theory [6062]. This is in contrast to
the sophisticated tools used by theoretical and computational
neuroscientists to study information processing by neural systems.
They have analyzed neural coding at multiple levels of detail, from
synapses, over spike trains in single neurons to information
processing at the network and at the systems levels [2,3,102104].
The methods used consider the neural system as a black box that
generates an input to output transform, an approach not
commonly used in systems biology. These tools allow for accurate
measurement and comparison of information transfer rates using
information theoretic analysis [3,105], detailed characterization of
optimal spatiotemporal input profiles using reverse correlation
methods [106] and independent component analysis [107,108],
and for definition of optimal coding schemes using Bayesian
methods [109] and infomax learning [110]. It is only recently that
information theoretic methods have started to enter the systems
biology domain [111,112]. One problem is that such methods
often require extensive manipulation of the input space, which
may be difficult to obtain in many biological experiments, but this
can be overcome by realistic modeling. For example, Mcell
modeling has been used to predict binding of attractant molecules
to cell receptors, which was then analyzed using information
theoretic tools to investigate what would be an optimal coding
scheme for chemotaxis [111]. In conclusion, the extensive
experience gained in studying neural coding principles may
inspire new methods to tackle the high dimensional information
processing problems encountered in almost every biological
system.

Looking Into the Future


How do we progress from here? Ideally one would want to
promote stronger interaction between the two fields and increased
awareness of each others strengths, i.e., by organizing joint
meetings. But at present it seems there is, exceptions like this
journal notwithstanding, little interest in the respective communities for such initiatives. In part, this reflects different interests,
e.g., system biologists often see computational neuroscience work

Acknowledgments
I wish to thank U. S. Bhalla, K. Doya, H. Kitano, N. Le Nove`re, T. Bartol,
and anonymous reviewers for valuable comments on earlier versions of this
manuscript.

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